Antiretroviral therapies with dideoxynucleosides, such as ZDV, have not been adequately examined for potential reproductive or long term mutagenic effects in humans. Such investigations are warranted given that genetic damage in humans and genetic plus reproductive effects in animals have been reported following ZDV exposure. The data obtained from such investigations help individuals and their physicians make more informed risk/benefit decisions about the use of these therapies. A total of 26 HIV positive males who were preparing to start nucleoside-containing antiretroviral therapy were enrolled in a study designed to measure cytogenetic damage in blood lymphocytes, and fertility and cytogenetic parameters in sperm. Blood and semen samples were obtained prior to the start of therapy and one to three times during treatment. Blood lymphocytes were processed for chromosome analysis and conventional analyses were performed on semen samples. Sperm smears were evaluated for abnormal morphology, and for aneuploidy using a novel fluorescence in situ hybridization (FISH) procedure. Sperm cells were also evaluated for chromosome breakage using another novel sperm-FISH assay. Analysis of the data revealed no significant treatment-related effects of antiretroviral therapy on lymphocyte or sperm cytogenetic parameters, or on semen volume or sperm concentration. However, sperm motility, viability, and morphology improved significantly with treatment. These findings suggest that nucleoside reverse transcriptase inhibitors, over a three-month period at currently recommended doses, do not adversely affect lymphocyte or sperm chromosomes, and may actually lead to improvements in semen quality. A manuscript describing the results of this study has been submitted to the Journal of Infectious Diseases.